Dendritic cells (DCs) capture pathogens in the mucosa and then migrate to the secondary lymphoid tissue, where they acquire the mature phenotype required to induce efficiently adaptive immune responses. The potential role of mature DCs (mDCs) uptake for antigen presentation implies efficient antigen capture and transfer into the antigen presentation pathway. Down regulation of endocytosis is considered a hallmark of DC maturation, but there is increasing evidence that under inflammatory conditions mDCs capture, process, and present antigens without exclusively relying on prior pathogen exposure. See Mellman I, et al., Cell 2001; 106:255-258, Platt C, et al., Proc. Natl. Acad. Sci. USA 2010; 107:4287-4292 and Drutman S, et al., J. Immunol. 2010; 185:2140-2146. This scenario might be particularly relevant in chronic infections, such as the one caused by HIV-1, where increased translocation of bacteria from the intestinal lumen could stimulate DCs systemically and contribute to sustained antiviral immune responses. See Brenchley J, et al., Nat. Med. 2006; 12:1365-1371.
Paradoxically, HIV-1 capture into mDCs appears to also critically enhance viral dissemination in lymphoid tissue by efficient presentation of infectious virus to T-cells in the DC-T-cell synapse, thus promoting pathogenesis and disease progression through trans-infection. In vitro studies have shown that, when HIV is incubated at low MOI with T cells, inclusion of DC results in much more efficient infection of the T cells. The mechanism for trans-infection has been a subject of some controversy. An HIV-1 gp120-independent mechanism of viral binding and uptake that is upregulated upon DC maturation has been previously identified in the art. See Izquierdo-Useros N, J. Virol. 2007; 81: 7559-7570. In addition, HIV-1 Gag eGFP-expressing fluorescent virus-like particles (VLPHIV-Gag-eGFP) follow the same trafficking route as wild type HIV-1 in mDCs, and hence share a common molecular pattern that governs entry into mDCs. See Izquierdo-Useros N, et al., Blood 2009; 113:2732-2741. However, the precise mechanism through which HIV-1 is internalized and accumulated into mDCs was unknown until now.
Accordingly, the identification of the mechanism by which uptake of HIV by DCs takes place would allow the development of tools useful for preventing said uptake, thus reducing the trans-infection of CD4+ T cells by DCs.